Mechanism of Didangtang in Inhibiting Aortic NLRP3 Inflammasome Cascade of Mice with Diabetic Macrovascular Disease / 中国实验方剂学杂志

Objective:To explore the progression of diabetic macrovascular disease and the effects of Didangtang at different doses on it. Method:Four-week-old male apolipoprotein-E knockout （ApoE^-/-） mice with diabetic macrovascular disease induced by exposure to high-fat diet combined with streptozotocin （STZ） were randomly divided into the model， simvastatin， as well as high-， medium-， and low-dose Didangtang groups. The age-matched ApoE^-/- mice of the same batch only fed with a high-fat diet were classified into the ApoE^-/- （model control） group， and C57BL/6 mice with the same genetic background receiving a regular diet into the normal group. The sampling was conducted at the 8th and 20th weeks of the experiment for observing the pathological characteristics of the aorta and the proportion of plaque area in mice of each group at different time points， followed by the comparison of blood glucose， blood lipid， and oxidized low-density lipoprotein （ox-LDL） levels. The aortic NOD-like receptor protein 3 （NLRP3） and cysteinyl aspartate-specific proteinase-1 （Caspase-1） protein expression was detected by Western blot assay， and the serum interleukin-1<italic>β</italic> （IL-1<italic>β</italic>）， interleukin-18 （IL-18）， interleukin-1<italic>α</italic> （IL-1<italic>α</italic>）， and tumor necrosis factor-<italic>α</italic> （TNF-<italic>α</italic>） levels by enzyme-linked immunosorbent assay （ELISA）. Result:The comparison with the normal group revealed that the proportions of plaque area in the ApoE^-/- group and the model group were increased （<italic>P</italic><0.01）， while the proportion of plaque area in each administration group was significantly reduced in contrast to that of the model group （<italic>P</italic><0.05）. The aortic NLRP3 and Caspase-1 protein expression levels as well as the serum IL-1<italic>β</italic>， IL-18， IL-1<italic>α</italic>， and TNF-<italic>α </italic>levels in the ApoE^-/- group and the model group were significantly higher than those in the normal group （<italic>P</italic><0.01）. Compared with the model group， each administration group exhibited a significant reduction in aortic NLRP3 and Caspase-1 protein expression and serum IL-1<italic>β</italic>， IL-18， IL-1<italic>α</italic>， and TNF-<italic>α</italic> levels （<italic>P</italic><0.05）， with the strongest inhibitory effect detected in the medium-dose Didangtang group （<italic>P</italic><0.05）. Conclusion:Didangtang directly alleviates diabetic macrovascular disease possibly by down-regulating NLRP3 and Caspase-1 protein expression and easing the inflammatory cascade.

Discussion on Regulating AGEs to Improve Diabetic Macrovascular Disease Based on Fu-xie Theory / 中国实验方剂学杂志

The long-term existence of hyperglycemia leads to the occurrence of metabolic memory effect， which is an important reason for the formation of diabetic macrovascular disease， so the early control of metabolic memory is the key to the prevention and treatment of diabetes and its complications. The excessive formation of advanced glycation end products （AGEs） is not only an important factor to cause metabolic memory， but also the core mechanism for diabetic macrovascular disease. It is believed in traditional Chinese medicine（TCM） that Fu-xie （incubative pathogen） is the key pathogenesis of the formation of diabetic vascular diseases， and it is necessary to adopt the principle of removing pathogenic factors and opening collaterals as early as possible to prevent and cure the disease. During the Spring and Autumn Period and the Warring States Period， the theory of Fu-xie was germinated， and got mature in the Ming and Qing dynasties after the continuous development. The so-called Fu-xie means that the pathogens are of a potential nature but not cause diseases immediately. The theory of Fu-xie first appeared in Huangdi Neijing， with an original meaning of epidemic febrile disease occurring after incubation， and then its meaning continues to expand， now referring to all potential pathogenic factors that would not immediately cause diseases. As the cause and pathogenesis of many diseases， the theory of Fu-xie is widely used in clinical practice to guide the treatment of diseases. In the body， the accumulation of AEGs can induce the subsequent cascade effect in the body， and finally promote the formation and development of diabetic macrovascular diseases. This is very similar to the process of inducing metabolic disorder and disease in TCM due to the accumulation of phlegm and silt. Therefore， under the guidance of Fu-xie theory， the mechanism of AEGs in blocking metabolic memory and preventing and treating diabetic macrovascular disease was analyzed in this paper. On the one hand， it will provide a scientific basis for the exploration of Fu-xie theory affecting the disease course of diabetic macrovascular disease by regulating the generation of AEGs. On the other hand， it can also provide the material change basis for the development of Fu-xie theory in the occurrence and development of diabetic macroangiopathy.

Mechanism of Danzhi Jiangtang Capsules in treatment of diabetic macrovascular disease in GK rats based on correlation between microRNAs and inflammatory factors / 中国中药杂志

This study was aimed to investigate the mechanism of Danzhi Jiangtang Capsules( DJC) in the treatment of diabetic macrovascular disease in Goto-Kakizaki( GK) rats. The diabetic macrovascular disease rat model was induced by feeding high-fat and high-sugar combined with endothelial nitric oxide synthase( NOS) inhibitor N-nitro-L-arginine methyl ester( L-NAME)( 0. 1 g·L-1·d-1). According to the random array table,the model rats were randomly divided into the model group,DJC groups( 1 260,630,320 mg·kg-1),atorvastatin group( 105 mg·kg-1) and metformin group( 10 mg·kg-1),with 12 rats in each group. The rats received gavage administration for 8 weeks. Twelve Wistar rats were selected as the normal control group. The changes of body weight,water intake,blood glucose,plasma total cholesterol( TC),triglyceride( TG),high density lipoprotein( HDL-C),low density lipoprotein( LDL-C),interleukin( IL-1β),IL-6,tumor necrosis factor( TNF-α),nitric oxide( NO),endothelin( ET-1) were observed in these rats. Aortic tissue was taken and the pathological changes were observed by HE staining. RT-PCR was used to detect the mRNA levels of IL-1β,IL-6,and TNF-α in rat aorta. RT-PCR of the stem loop was used to detect the levels of miRNA-126,miRNA-155,miRNA-146 a,and miRNA-21 in rat plasma and aortic tissue. The canonical correlation between miRNAs and inflammatory factors was then analyzed. The results showed that DJC increased the rat body weight,lowered water intake,reduced the random blood glucose,reversed the rat aorta tissue damage,reduced serum TC,TG,LDL-C,ET-1,IL-1β,IL-6,TNF-α,as well as miRNA-155,miRNA-146 a and miRNA-21 levels in serum,elevated plasma HDL-C,NO content,reduced the aorta mRNA of IL-1β,IL-6,TNF-α,and the miRNA-155,miRNA-146 a and miRNA-21,elevated miRNA-126 expression in aorta. Aortic miRNA-126,miRNA-155,miRNA-146 a and miRNA-21 expression levels were typically correlated with the expression of inflammatory factors,among which miRNA-126 was negatively correlated,miRNA-155,miRNA-146 a and miRNA-21 were positively correlated with the factors. These results suggested that DJC had therapeutic effects on diabetic macrovascular diseases,and the mechanism of action may be related to the regulation of miRNA-126,miRNA-155,miRNA-146 a and miRNA-21 levels,as well as the reduction of inflammatory factors and vascular inflammatory response.

Study progress of traditional Chinese medicine treating type 2 diabetes macrovascular disease / 国际中医中药杂志

Type 2 diabetes macrovascular disease is the main cause of death in type 2 diabetes mellitus. In recent years, the modern medical research and treatment of type 2 diabetes macrovascular disease has made some progress, but the international clinical trials suggest that the current treatment can not effectively reduce the incidence of this disease. Many clinical practices show that the effect of traditional Chinese medicine on this disease is exact, so that the clinical workers on the treatment of type 2 diabetes mellitus macrovascular disease of the status quo, now from the etiology and pathogenesis,clinical research, experimental research on the literature published in recent years, to provide reference for clinical treatment.

Effect of calcitriol on subclinical macrovascular disease in type 2 diabetic patients / 中华内分泌代谢杂志

The changes of carotid intima media thickness (cIMT) in type 2 diabetic patients with vitamin D insufficiency and subclinical macrovascular disease after 12 months' intervention therapy with calcitriol were observed.86 patients with vitamin D insufficiency [25 (OH) D＜30 ng/ml] and subclinical macrovascular disease were randomized to group A (n =44,treated with 0.5 μg/day calcitriol) or group B (n =42,blank control) for 12 months.40 patients in each group completed the follow up.After 12 months of therapy with calcitriol (0.5 μg.qd.po.),levels of high sensitive-Creactive protein,sCD36,and cIMT were significantly decreased,while 25 (OH) D and ankle brachial index were significantly increased (P＜0.05) in group A,suggesting that calcitriol could improve cIMT in patients with vitamin D insufficiency and subclinical macrovascular disease.

Pattern of macrovascular disease phenotypes amongst newly diagnosed type 2 diabetic patients in a rural institute in Uttar Pradesh, India.

Background: The objective of current study was to determine the proportion of Macrovascular Disease (MVD) phenotypes amongst newly diagnosed type 2 diabetic patients in our institute by dividing the cases into sub-groups according to the MVD sites involved (NMVD - no macrovascular disease; NSCS - non-significant carotid stenosis; CBVD - cerebrovascular disease; CAD - coronary artery disease; PAD - peripheral artery disease; PVD - polyvascular disease) and studying the anthropometric, clinical and laboratory parameters in each group. Methods: The study included a cohort of 136 newly diagnosed patients with T2 DM. Demographic, clinical and laboratory parameters were included in analyses. Standardized procedures were used to assess the risk factors of associated metabolic syndrome (MetS). Results: The proportion of patients with MVD was 27.94% amongst the participants in the study. The majority of patients with MVD were in the CAD group (15.44%). Age, male sex and smoking history were independent risk factors in the CAD and PAD groups (P <0.01). A low HDL-C value was an independent risk factor in the CAD and PVD group P = 0.03). Very high frequencies of MetS were observed in the PAD and PVD groups (90% and 91.7% respectively). Prevalence of PVD was three times more common in males as compared to that in females. All patients with PAD had associated CAD also. Conclusion: This study projects a high proportion of MVD amongst newly diagnosed Type 2 diabetics in rural sub-population in Uttar Pradesh. High rates of mortality and morbidity in these patients due to macroangiopathy warrant early screening of MVD to ensure timely preventive and therapeutic measures.

Relationship between vascular disease and uric acid of type 2 diabetic patients / 中国综合临床

Objective To investigate the correlation between uric acid level and macrovascular disease in type 2 diabetic patients.Methods Sixty type 2 diabetic patients with lower limb atherosclerosis of carotid artery were randomly selected in study group who hospitalized in the First Hospital of Zibo from Mar.to Feb.2012.Sixty type 2 diabetes mellitus(T2DM) without carotid and lower limb athemsclerosis were served as control group.The blood pressure,blood lipid,blood glucose and other biochemical indexes,including blood uric acid,serum insulin (FNS),fasting blood glucose (FPG),apolipoprotein a (LP (a)),apolipoprotein A1,B (APO-A1,APO-B),glycosylated hemoglobin (HbA1c),high density lipoprotein cholesterol (HDL-C),low density lipopmtein cholesterol (LDL-C),triacylglycerol (TG) and total cholesterol (TC) were measured and determined.Results There was no significant difference in terms of blood pressure,blood lipid levels,APO-A1,APO-B,HbA1C,FNS and FPG in study group patiems (P ＞ 0.05).The level LP(a) in study group was (0.4 ± 0.2) g/L,significantly higher than that in control group ((0.2 ± 0.2) g/L; t =3.842,P ＜ 0.01).The blood uric acid level in study group was (362.3 ± 112.8)mmol/L,significantly higher than that of the control group((284.8 ±68.6)mmol/L;t =3.188,P＜0.01).Conclusion Uric acid and LP(a) are involved in the oocurrence and development of athemsclemsis,which is close related to the development of type 2 diabetic macmangiopathy.Therefore,in the process of preventing type 2 diabetes with macroangiopathy,we should pay attention to uric acid and LP (a) of the patient beside effective control of blood glucose,blood pressure,blood lipid level.

The Analysis for Macrovascular Disease in Newly Diagnosed Type 2 Diabetic Patients / 中国基层医药

ObjectiveTo investigate the risk factors associated with macrovascular disease in patients with newly-diagnosed type 2 diabetes. MethodsAccording to arterial intima-media thickness(IMT)measured by color duplex ultrasonography,232 cases of newly-diagnosed type 2 diabetic patients were divided into two groups:one group were 95 cases with macrovascular disease(MD),and the other group were 137 cases without macrovascular disease (non-MD).Then various clinical data between the two groups were compared and the correlated risk factors for macrovascular disease were analyzed. Results (1)95 patients(40.9%)showed macrovascular disease in 232 patients.(2)Age,BMI,SI,systolic blood pressure,diastolic blood pressure,TC,LDL-C,CRP and 24h UmAlb were significantly higher in MD group compared with those in non-MD group(all P＜0.05);But ISI was significantly lower in MD group compared with that in non-MD group(P＜0.05).(3)Pearson correlation analysis showed that risk factors were old age,BMI,smoking,higher systolic blood pressure,higher diastolic blood pressure,TC,LDL-C,CRP and microalbuminuria. ConclusionMacrovascular disease was related to many factors.It was important to control some risk factors earlier for preventing the happening and progress of macrovascular disease.

Consumo alimentar e doença macrovascular em nipo-brasileiros: um estudo transversal / Dietary intake and macrovascular disease in a Japanese-Brazilian population: a cross-sectional study

OBJETIVO: Descrever o hábito alimentar de nipo-brasileiros com e sem doença macrovascular (DMV). MÉTODOS: Definiu-se DMV, para 1.165 nipo-brasileiros, a partir de escores atribuídos ao histórico de saúde, eletrocardiograma e valores do índice tornozelo-braquial. Determinou-se o consumo alimentar habitual por meio de Questionário de Frequência do Consumo de Alimentos. RESULTADOS: A porcentagem de casos confirmados com DMV foi de 3,2 por cento, sendo semelhante entre os sexos. Observou-se, de forma estatisticamente significante, maior frequência de indivíduos com DMV (confirmados ou suspeitos) entre aqueles de primeira geração, com idade > 60 anos, tabagistas, com hipertensão arterial, hipertrigliceridemia e diabetes. Nipo-brasileiros com DMV (confirmados ou suspeitos) apresentaram menor perímetro do quadril e maior idade, pressão arterial sistólica, triglicérides, glicemia, consumo de alimentos fonte de ferro e menor fonte de fibras de grãos. Encontrou-se diferença estatisticamente significante apenas para o consumo de gordura saturada (análise bruta: segundo terço versus primeiro terço). CONCLUSÕES: programas de educação nutricional devem ser incentivados neste grupo com alta prevalência de doenças crônicas não transmissíveis.

OBJECTIVE: To describe the food intake of Japanese-Brazilians with and without macrovascular disease (MVD). METHODS: MVD was defined, for 1,165 Japanese-Brazilians, by scores attributed to the health historical, electrocardiogram and ankle-brachial index values. The usual dietary intake was determined using a food frequency questionnaire. RESULTS: The MVD prevalence was of 3.2 percent, being similar among genders. Statistically higher frequencies of individuals with MVD were observed among those of first generation, with age > 60 years, tobacco user, with hypertension, hypertriglyceridemia and diabetes. Subjects with MVD were older, with smaller hip circumference, and higher systolic blood pressure levels, triglycerides and glycemia concentration; they informed higher consumption of iron source food and smaller of grains fibers. Statistically significant difference was found to saturated fat (crude analysis: second tercile versus first tercile). CONCLUSIONS: Programs of nutritional education should be stimulated in this group with high prevalence of non-communicable chronic diseases.

Estudo da macrovasculatura por ultra-sonografia Doppler na esclerose sistêmica / Study of macrovasculature by Doppler ultrasound in systemic sclerosis

OBJETIVO: Avaliar a ocorrência e a distribuição das alterações macrovasculares em uma população com esclerose sistêmica (ES) por meio da ultra-sonografia Doppler (USG Doppler) e do índice tornozelo-braço (ITB). Foi investigada a associação destes achados com as características demográficas e clínicas dos pacientes, bem como fatores de risco e antecedentes da doença ateromatosa. MÉTODOS: Estudo prospectivo, tipo série de casos, constituído de 20 pacientes, sendo 19 do sexo feminino, com idade média de 46,30 anos. A forma clínica difusa esteve presente em 85 por cento dos pacientes. Todos tinham fenômeno de Raynaud (FR), 55 por cento apresentaram alteração de polpas digitais, 15 por cento úlcera atual de membros e 25 por cento reabsorção de falange. Não houve amputação e 70 por cento apresentaram de um a quatro fatores de risco de aterosclerose. A aorta, as carótidas, bem como as artérias dos membros superiores (MMSS) e inferiores (MMII) foram estudadas por USG Doppler para a avaliação de espessamento do complexo íntima-medial (CIM), presença de placas e aneurismas. Nas artérias dos MMII, foi também realizado o ITB. RESULTADOS: O ITB foi normal em todos os pacientes, entretanto 12 (60 por cento) destes apresentaram doença macrovascular (DMV), sendo 9 (45 por cento) na aorta, 7 (35 por cento) nos MMII, 6 (30 por cento) nas carótidas e 1 (5 por cento) nas artérias dos MMSS. Observou-se associação entre DMV e alterações de polpas digitais (p = 0,0045). CONCLUSÕES: A USG Doppler identificou DMV em 60 por cento dos pacientes com ES. Nenhum paciente apresentou ITB anormal. Verificou-se associação significante da DMV com as alterações atuais de polpas digitais. As alterações macrovasculares encontradas não estão necessariamente associadas à esclerose sistêmica e podem decorrer do processo aterosclerótico.

OBJECTIVE: To assess the occurrence and distribution of the macrovascular alterations in a population with Systemic Sclerosis (SS) by means of Doppler ultrasound (Doppler US) and ankle-arm index (AAI). To investigate the assotiation of these findings with both demographic and clinical characteristics in the patients as well as with risk factors and antecedents of atheromatous disease. METHODS: Prospective study, of the series of cases type, comprising 20 patients, 19 of whom were women with a median age of 46.30 years. Eighty-five percent were of the diffuse form. All the patients had the Raynaud's phenomenon, 55 percent presented alteration of digital pulps, 15 percent current limb ulcers and 25 percent phalanx resorption. There were no amputations and 70 percent presented from 1 to 4 risk factors for atherosclerosis. The aorta, carotids as well as upper (ULs) and lower (LLs) limbs arteries were evaluated by Doppler US to assess thickening of the medio-intimal complex (MIC), presence of plaques and aneurisms. In the arteries of the LLs, AAI was also undertaken. RESULTS: AAI was normal in all patients, 12 patients (60 percent) presented macrovascular disease (MVD) comprising 9 (45 percent) of these in the aorta, 7 (35 percent) in LLs arteries , 6 (30 percent) in the carotids and 1 (5 percent) in ULs arteries. MVD and alterations of digital pulps were positivily associated (p = 0.0045). CONCLUSIONS: Doppler US identified MVD in 60 percent of our SS patients. No patients had abnormal AAI. MDV was positivily associated with digital pulps alterations. The macrovascular alterations found are not necessarily associated with systemic sclerosis, and may be due to atherosclerosis process.

High sensitive Serum C-reaction protein in macrovascular disease with or without type 2 diabetes / 中国康复理论与实践

@#ObjectiveTo observe the changes of high sensitive serum C-reaction protein (hsCRP) in macrovascular disease with or without type 2 diabetes.MethodsThere were 3 groups population in our study:148 type 2 diabetic patients were divided into 2 subgroups:77 patients with macrovascular disease and 71 without macrovascular disease, 73 non-diabetic patients with macrovascular disease and 75 health controls. The concentration of serum hsCRP of all patients were determined by ELISA.ResultsThere was significant difference in concentration of serum hsCRP between type 2 diabetes with or without macrovascular disease groups, non-diabetes macrovascular disease group and control(P<0.01 or P<0.001). However, there was not significant difference between 2 diabetes groups and non- diabetic macrovascular disease group(P>0.05). There was no significant difference in hsCRP between type 2 diabetes with and without macrovascular disease (P>0.05).ConclusionThere may be a chronic inflammatory reaction in patients with type 2 diabetes or macrovascular disease. hsCRP might be a well forecasting factor of the occurrence and development of type 2 diabetes and atherosclerosis.

MTHFR gene polymorphism as a risk factor for diabetic nephropathy and macrovascular disease in NIDDM patient / 대한내과학회지

BACKGROUND: Diabetic nephropathy develops in 20-30% of patients with non-insulin dependent diabetes mellitus (NIDDM). Poor glycemic control, hypertension and duration of diabetes are known as risk factors for the development of diabetic nephropathy and there is high prevalence of diabetic nephropathy in the patients who have familial history of diabetic nephropathy, so it has been assumed that genetic factor is associated with the background of its occurences. Recently it has been observed that a cytosine to thymidine substitution of the methylenetetrahydrofolate reductase (MTHFR) gene at nucleotide 677 (C677T) was related to diabetic nephropathy in patients with NIDDM and MTHFR gene polymorphism was also known to predispose to vascular disease. This study was performed to investigate whether MTHFR gene polymorphism is associated with the development of diabetic nephropathy and macrovascular disease in NIDDM patients. METHODS: The study population consisted of 243 NIDDM patients (duration> OR = 10 years). Nephropathy was defined by 24 hour urinary protein excretion of more than 500 mg. The MTHFR gene fragment was extracted using the polymerase chain reaction. The presence of the mutation was identified by HinfI digestion, which cuts at the mutation site, followed by 2.5% metaphore agarose electrophoresis and ethidium bromide staining. Statistical differences in genotype distribution and allele frequencies among the groups were assessed by the chi-square test. RESULTS: There was no difference in clinical characteristics except the prevalence of hypertension and diabetic retinopathy between nephropathy group and non-nephropathy group. The data do not show any difference of genotype distribution or allele frequencies between patients with or without diabetic nephropathy and macrovascular disease CONCLUSION: With the above results, it is assumed that there are no significant relationships among MTHFR gene polymorphism, diabetic nephropathy, and macrovascular disease.

Association of Macrovascular Disease with Serum Lipoprotein(a) Levels in the Elderly

BACKGROUND : Lipoprotein(a)[Lp(a)] may be an independent risk factor for macrovascular disease in middle aged populations, but in elderly populations, Lp(a) levels to predict macrovascular risk is controversial. The purpose of this study is to evaluate the association of macrovascular disease with Lp(a) levels and lipid change in the elderly. METHODS : We have examined Lp(a) levels, lipid change and clinical, biochemical profile in 114 patients with macrovascular disease and 55 control subjects. Macrovascular disease was defined as ishemic heart disease and/or peripheral vascular disease, peripheral vascular disease was defined as arteriosclerosis obliterans, diabetic foot and/or cerebrovascular disease. RESULTS : Hypertension, diabetes were more prevalent and median Lp(a) levels, fasting blood glucose and HDL-cholesterol were significant higher in patients with macrovascular disease than control subjects, but there were no significant differences in age, body mass index, total cholesterol and triglycerides levels. Lp(a) levels were positively weak correlated with fibrinogen levels, but not correlated with age, body mass index, total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides levels. In logistic regression analysis, there was no independent risk factor for ischemic heart disease, whereas diabetes, hypertension and low HDL-cholesterol levels were independent risk factors for peripheral vascular disease. CONCLUSION : Serum Lp(a) levels was not independent risk factor for macrovascular disease, but diabetes, hypertension and low HDL-cholesterol levels were independent risk factors for peripheral vascular disease. Therefore, the relationship between Lp(a) and lipid change and macrovascular disease in the elderly were different from middle aged subjects.